Hepatic encephalopathy (HE), also known as portosystemic encephalopathy, is a severe complication of acute or chronic liver failure.
Patients suffer from various neurologic and neuropsychiatric abnormalities (asterixis, confusion, altered level of consciousness, coma as a result of liver failure).
During cirrhosis, hepatic encephalopathy negatively impacts patient survival. About 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma.
Consequently, the economic burden of hepatic encephalopathy is substantial, as it is the second most common reason for hospitalization of cirrhotic patients in the United States.
Hepatic encephalopathies can be subdivided in type A, B and C depending on the underlying cause.
Type A (=acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema. Acute liver failure is a rapid deterioration (within days and weeks) of liver function in a person who had no pre-existing liver disease. Acute liver failure is commonly caused by paracetamol (acetaminophen) overdose, idiosyncratic reaction to medication (e.g. tetracycline, troglitazone), autoimmune causes, viral hepatitis (hepatitis A or B), acute fatty liver of pregnancy, or can be idiopathic.
Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease. The blood thus by-passes the liver, which therefore cannot metabolize and clear blood substances which can be toxic like ammonium. Type B usually occurs as a result of congenital abnormalities and/or as a result of an invasive procedure or trauma.
Type C (=cirrhosis) occurs in patients with cirrhosis. Cirrhosis is a late stage of chronic liver disease when scarring (fibrosis) develops. The major causes of cirrhosis are:                chronic alcoholism        viral infections caused by chronic viral hepatitis (types B, C and D)        metabolic diseases such as NASH (Non Alcoholic Steato Hepatitis)        alpha-1-antitrypsin deficiency, galactosemia and glycogen storage disorders        inherited diseases such as Wilson disease and hemochromatosis        biliary cirrhosis resulting from diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC)        toxic hepatitis caused by severe reactions to prescribed drugs or prolonged exposure to environmental toxins        repeated bouts of heart failure with liver congestion.        
Type-C HE can be subdivided in episodic (return to normal neural state between episodes), persistent (no return to normal neural state) and minimal encephalopathy (Bajaj, Aliment Pharmacol Ther. 2010 March; 31(5):537-47).
Minimal encephalopathy is an encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be evidenced using neuropsychological tests, and has been demonstrated to impair quality of life and to increase the risk of involvement in road traffic accidents.
Minimal HE may affect 30-70% of patients with cirrhosis; overt HE (either episodic or persistent) is observed in 30-45% of patients with cirrhosis during their lifetime. It is to be noted that HE, even minimal, is an independent risk of mortality.
The physiopathology of hepatic encephalopathy is still debated but many hypothesis are studied. Ammonia may have a central key role, together with systemic inflammation and changes in specific carriers on the blood-brain barrier. Hepatic encephalopathy could be a consequence of accumulation in the bloodstream of toxic substances, in particular ammonia, that are normally cleared by the liver. Ammonemia is not sufficient to induce HE. It is hypothetized that a combination of both increased blood ammonia and inflammation is necessary for HE to occur, in particular by a modification of the blood-brain barrier leading to intracerebral accumulation of toxic substances and modulation of neurotransmission.
Treatments of Hepatic Encephalopathy
Most specific current therapies are designed to decrease intestinal ammonia production and the resulting hyperammonemia.
During acute hepatic encephalopathy, lactulose (beta-galactosidofructose) or lactilol (beta-galactosidosorbitol) are given to patients to accelerate the transit and to inhibit intestinal ammonia production. These are nonabsorbable disaccharides that are degraded by intestinal bacteria to lactic acid and other organic acids. Lactulose is administered to patients at a dose of 30 mL orally, daily or twice daily, and the dose may be increased, or reduced, depending on the tolerance or adverse effect observed in the patients.
Higher doses of lactulose (60 mL every eight hours) may be administered to patients with severe hepatic encephalopathy. Lactulose is given after the first episode of hepatic encephalopathy to prevent recurrence.
Various antibiotics are also used, in order to decrease the ammoniagenic bacterial load. Antiobiotics are generally used if treatment with lactulose is not effective enough and in secondary prevention.
One can use neomycin, metronidazole, rifaximin, oral vancomycin, paromomycin, and oral quinolones. Rifaximin a nonabsorbable derivative of rifampin with a broad spectrum antibacterial activity. It can reduce endotoxemia, including hyperammonemia, by reducing the intestinal translocation of bacteria. Used in a number of trials, rifaximin effect was equivalent or superior to the compared agents with good tolerability. The recommended posology is 550 mg twice a day.
Recently, therapies used for the treatment of inborn errors of urea metabolism begin to be used in patients with hepathic encephalopathy, but are not yet formally recommended. These include:                A stable salt of 2 constituent amino acids, L-ornithine and L-aspartate (LOLA), can also be used to increase ammonia clearance. It may be combined with lactulose and/or rifaximin.        Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate, and glycerol phenylbutyrate may also be used for the treatment of hepatic encephalopathy. The oral doses of sodium benzoate are about 5 g twice a day, although lower doses (2.5 g three times a week) may also help patients recover from symptoms of hepatic encephalopathy. Glycerol phenylbutyrate may be used at an oral dose of 6 ml twice-daily.        
Nutritional intervention is necessary in case of malnutrition or insufficient dietary intake. Eating vegetables proteins rather than proteins derived from red meat, and chicken and fish proteins may be favourable. It is also advised to supplement the diet with branched-chain amino acids. Zinc administration can also be used, with the potential to improve hyperammonemia, with zinc sulfate and zinc acetate that can be administered at a dose of 600 mg orally every day. L-carnitine is also used to improve hepatic encephalopathy symptoms, in particular in patients with cirrhosis.
WO 2011/124571 describes the use of biotin at a high dose (in the range of 100 to 600 mg/day) for the treatment of visual impairments, in particular related to optic atrophy. It should be noted that the visual impairments actually described in this application are symptoms related to a particular leukoencephalopathy, i.e. an involvement of the white matter of the brain. This document neither describes nor suggests that biotin could be used for the treatment of HE.
WO 2014/016003 describes the use of biotin at a high dose (of the order of 100 to 600 mg/day) for the treatment of multiple sclerosis (MS), stroke and X-linked adrenoleukodystrophy (X-ALD), in particular adrenomyeloneuropathy (AMN).
WO 2014/177286 provides evidence that biotin is useful for treatment of AMN.
WO2016151132 provides evidence that biotin is useful for treating amyotrophic lateral sclerosis (ALS).
Nagamine et al (J Gastroenterol. 1995 June; 30(3):351-5; and Nihon Shokakibyo Gakkai Zasshi. 1989 July; 86(7):1519-24) and in JPH01226814A have induced acute hyperammonemia in rats by administering urease or ammonium acetate. In another model, acute liver failure was induced by injecting a single high dose of CCl4. The authors observed an ability of biotin to decrease the serum ammonium level in this animal acute liver failure model. The amount of biotin when administered was not controlled when given orally and was 0.5 mg/kg BW (body weight) when a single dosed was injected intraperitoneally (Nagamine, 1989). In Nagamine (1995), the dose of biotin (provided as a single intraperitoneal shoot) is also very low.
In JPH01226814A, the biotin is provided as a single intraperitoneal shoot of 1 mg of biotin. Results are reported for human, with doses used therein in the range of a few mg (about 5-10 mg) per day. The results reported for the patients are, however, not conclusive. Indeed, there is a high natural variability of the general state and of the ammonia level in the serum of patients with HE. Tables 7 and 8 only report data obtained during 10 days, without any control or information about other treatments that the patients received. From patient 2, it can be seen that there is a high variability in the ammonia level (rising and decreasing) for the first 5 days, even tough this patient did not receive any biotin during this timespan. It is also true for patient 3, where ammonia level had well decreased between days 48 and 96 although no biotin had been administered to the patient in this timespan. There is thus no possibility to reach a conclusion on the actual role of biotin on ammonia levels and for controlling HE in these patients.
It is further to be noted that despite the results reported therein more than 20 years ago, no drug based on biotin was developed or proposed to the market to treat or prevent hepatic encephalopathy.
In particular, a review by Bajaj (2010, Aliment Pharmacol Ther 31, 537-547) does not mention biotin as a product that is or can be used for the treatment of type C hepatic encephalopathy.